NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation

Rachel Cooney. et al. 2010. Nature Medicine. 16, 90-97

Student: Yu-Ping Chang (張鈺苹)                                 Time: 16:00~17:00, Apr. 14, 2010

Commentator: Dr. Huan-Yao Lei (黎煥耀 博士)        Place: Room 601

Abstract:

Nucleotide-binding oligomerization domain-containing-2 (NOD2) is an intracellular pattern recognition receptor which acts as a bacterial sensor. However, it remains unclear how antigens to be present after pathogens are recognized by NOD2. NOD2 was found to be the first gene associated with Crohn’s disease which is a human intestinal inflammatory disease¹. Recent genome-wide association studies define more than 30 distinct susceptibility loci for Crohn’s disease including an unexpected autophagy-related gene ATG16L1². Autophagy is a physiological process, which mediates cytosolic component degradation, pathogens recognition and antigen presentation³. The authors found that NOD2 was required for muramlydipeptide (MDP)-induced autophagy in primary human antigen-presenting cells, monocyte-derived dendritic cells (DCs). Autophagy-related protein-5, -7, and -16L1 and receptor-interacting serine-threonine kinase-2 but not NOD-like receptors family, pyrin domain containing-3 (NALP3) were required for MDP-induced autophagy. MDP-treatment increased the level of MHC class II (HLA-DR) but not MHC class I expression. Furthermore, infection of live attenuated recombinant S. enterica serovar typhimuriun aroA aroD mutant expressing the carboxy-terminal fragment of tetanus toxin in NOD2 or ATG16L1 knockdown DCs showed significant reduction on antigen-specific proliferative responses. DCs obtained from individual with Crohn’s disease expressing variant NOD2 (1007fsinsC, R702W and G908R) were failed to induce HLA-DR colocalized with LC3 and were unable to up-regulate surface MHC class II expression. Proliferation of tetanus toxin-specific CD4⁺ Tcell was also reduced. DCs that expressed Crohn’s disease-associated susceptibility variant ATG16L1 T300A was also shown similar defect to NOD2 variants. The localization of either S. enterica or adherent-invasive E. coli with lysosomes in DCs expressed NOD2 variants were much lower than DCs expressed wild-type NOD2. NOD2 variants of DCs showed a decrease for bacterial handling ability. Taken together, the authors linked two of the strongest genetic risk factors in Crohn’s disease to a single signaling pathway.

References:

1.      Hugot, J.P. et al. 2001. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411, 599–603.

2.      Barrett J.C. et al. 2008. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat. Genet. 40, 955–62.

3.      Schmid, D. et al. 2007. Innate and adaptive immunity through autophagy. Immunity 27, 11–21.